Amphetamine effects on startle gating in normal women and female rats

Abstract

Background: Dopamine agonists disrupt prepulse inhibition (PPI) of startle in male rodents. In humans, this is observed only in some studies. We reported that PPI was disrupted by D: -amphetamine in men, but only among those with high basal PPI levels. Here, amphetamine effects on PPI were tested in normal women and female rats.

Materials and methods: Acoustic startle and PPI were tested in normal women after placebo or 20 mg amphetamine, in a double-blind, crossover design, and in female rats after vehicle or 4.5 mg/kg amphetamine. Rats were from Sprague-Dawley (SD) and Long Evans (LE) strains that differ significantly in gene expression in PPI-regulatory circuitry, including levels of nucleus accumbens (NAC) catechol-O-methyl transferase (COMT) mRNA.

Results: Amphetamine was bioactive in humans based on quantitative autonomic and self-rating measures, but did not significantly change startle magnitude or PPI across all subjects. Amphetamine's effects on PPI in women correlated significantly (p < 0.0008) with placebo PPI levels (reducing PPI only in women whose basal PPI levels exceeded the sample median) and with measures of novelty and sensation seeking. Amphetamine decreased PPI in SD rats that have relatively low NAC COMT gene expression and increased PPI in LE rats that have relatively high NAC COMT gene expression.

Conclusion: The dopaminergic regulation of PPI in humans is related to basal levels of sensorimotor gating and to specific personality traits in normal men and women. In rats, the effects of amphetamine on PPI differ significantly in strains with low vs. high NAC COMT expression.

Figures

Fig. 1

Evidence of bioactivity of 20 mg AMPH in this study. a AMPH prevented the drowsiness normally experienced by test subjects. b AMPH also reduced blink rate, an effect likely linked to a reduction in drowsiness. c AMPH also increased heart rate (BPM beats per minute), and both diastolic and systolic blood pressure (DBP and SBPP, respectively, in mm)

Fig. 2

Effects of AMPH (“drug”) vs. placebo on PPI among subgroups defined by median split of mean placebo PPI level. AMPH significantly reduced PPI among “high-gating” subjects (p<0.003); in “low-gating” subjects, PPI-enhancing effects of AMPH did not reach significance, despite effect sizes between 0.55 and 0.79 for 20, 30, and 60 ms prepulse intervals. Regression analysis across all subjects revealed a highly significant correlation between higher baseline PPI level and greater PPI-reducing effects of AMPH (R=0.74, p<0.0008). Inset shows no significant effect of AMPH on startle magnitude in low- or high-gating subgroups

Fig. 3

AMPH effects on PPI among subgroups based on median split of personality scale scores. a ANOVA revealed significant PPI-reducing effects of AMPH in subgroups characterized by high NS scores (p<0.003). AMPH effects on PPI correlated significantly with NS scores (higher NS score associated with greater PPI-reducing effects of AMPH, R=0.54, p<0.027. Inset shows no significant effect of AMPH on startle magnitude in low or high NS subgroups. b Statistically comparable findings were detected using median split analyses for SSS scores (significant PPI-reducing effects of AMPH in the subgroup characterized by high SSS scores (p<0.04), and AMPH effects on PPI correlated significantly with SSS scores (higher total SSS scores associated with greater PPI-reducing effects of AMPH (R= 0.64, p<0.006)), and no significant effect of AMPH on startle magnitude in low or high SSS subgroups)

Fig. 4

AMPH effects on PPI in female SD and LE rats, divided by strain (a) and low vs. high baseline PPI levels (b). SD and LE rats differ significantly in the expression of a number of DA-linked genes in the nucleus accumbens; for example, expression of COMT mRNA is significantly lower in SD vs. LE rats (p<10−17). a ANOVA revealed significant PPI-reducing effects of AMPH in SD rats (p< 0.04), and PPI-increasing effects of AMPH in LE rats for the 20-ms prepulse interval (p<0.03). Inset shows no significant effects of AMPH on startle magnitude in SD or LE rats. b ANOVA revealed significant PPI-reducing effects of AMPH in rats with high baseline PPI (SD:LE=6:4; p<0.035), and PPI-increasing effects of AMPH in low-gating rats for the 10–20-ms prepulse intervals (SD:LE=4:6; p< 0.05). Inset shows no significant effects of AMPH on startle magnitude in low- or high-gating rats